We plan to assess several areas of importance to the field of alcoholism and its effects. 1) Sedatives in Health and Liver Disease. Alcohol and benzodiazepines seem to summate in their sedative effects. We will determine if alcohol acutely in experimental animals and in man interferes with the elimination of benzodiazepines which are inactivated by glucuronidation. The rationale of this are the observations that glucuronidation is well preserved in patients with liver disease but theoretically alcohol metabolism may decrease the availability of uridine diphosphoglucuronic acid, the substrate for glucuronidation. Accordingly we will determine the effects of acute alcohol administration on the elimination of oxazepam and lorazepam, two benzodiazepines which in man and dog are inactivated solely by glucuronidation. Other studies in patients with alcoholic liver disease will be directed at assessing the effects of the disease on the elimination of morphine, which also is metabolized to a glucuronide. 2) Fetal-Alcohol syndrome. We will continue to assess both in vitro with rat placental chuncks and in vivo the effects of alcohol and of acetaldehyde on the transport of various aminio acids, caffeine, nicotine and other drugs which could contribute to the development of this syndrome. 3) Hepatic Encephalopathy. We will assess the possibility that various amino acids (i.e., tryptophan, methionine, aromatic amino acids) and their derivatives (which are present in excess in patients with hepatic encephalopathy) may compete with endogenous alerting substances in brain for binding to receptors for gamma aminobutyric acid, opiates and other substances. It is our hope to elucidate the pathogenesis of the encephalopathy.